6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo(b,d)-pyrans

ABSTRACT

THIS INVENTION IS DIRECTED TO A PROCESS OF PRODUCING (-)-1-HYDROXY-3-N-AMYL-6,6,9-TRIMETHYL-6A,10A-TRANS6A,7,8,10A -TETRAHYDRODIBENZO(B,D)-PYRAN AND RELATED PYRANS FROM RESORCINOLS, INCLUDING INTERMEDIATES THEREIN. THE PYRANS PRODUCED BY THIS INVENTION POSSESS PSYCHOTOMIMETIC AND ANALGESIC ACTIVITY.

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United States I ?atent 3,833,616 6a,10a-TRANS-6a,7,8,10a-TETRAHYDRO- I RANS- Theodor Petrzilka, 6 Rigistrasse, Erlenbach, Switzerland No Drawing. Continuation-impart 'of abandoned application Ser. No. 760,055, Sept. 16, 1968.'This application Feb. 1, 1971, Ser; No. 111,669' P Int. Cl. C07d 7/20 US. Cl. 260----345.3

ABSTRACT on THE ms'cL'osURE This invention is directed to a,process of producing ()-1-hydroxy-3-n-amyl-6,6,9 triniethyl 6a,10atrans- 6a,7,8,10a tetrahydrodibenzo(b,d) pyran and related pyrans from-resorcinols, including intermediates therein. 1

The pyrans produced. by this invention possess psychotomimetic and analgesic activity.

RELATED APPLICATIONS This application is a continuation-in-part application of co-pending application Ser. No; 760,055, filed Sept. 16, 1968, now abandoned.

BACKGROUND OF THE INVENTION In US. Pat. No. 3,388,136 issued June 11, 1968, there is disclosed a method for preparing racemic trans tetrahydro-Ga,10a,dibenzo-(b,d)-pyrans. The trans racemate is obtained when separating a mixture of cis and trans racemates obtained by a process described in the patent utilizing vapor phase chromatography. However, the patent contains no indication as to how the ()-trans isomer can 3,833,616 Patented Sept. 3, 1974 ice SUMMARY OF THE INVENTION In accordance with this invention, it has been discovered that compounds of the formula:

1 to 10 carbon atoms,

' can be synthesized from compounds of the formula:

be placed in the possession of the art. The present inven- I tion on'the other hand, provides the art for the first time with the ()-trans isomer in substantially pure form and being substantially free of the (+)-trans optical antipode.

The crude resin obtained from the flowering tops of female plants of several Cannabis sativa L. varieties has been known and used as a psychotomimetic agent for many years. The structure of this material known variously as marihuana, hashish, etc. had evaded elucidation for many years. Advanced techniques in the field of molecular structural identification such as nmr have led to the identi fication of the active ingredients of the various sativa L. varieties. Gaoni et al. in J. Am. Chem. Soc., 86, 1646 (1964) identified one of the psychotomimetically active components extracted from varieties of Mexican hemp as:

wherein R is n-amyl.

Since the source of hashish or marihuana has been from the extraction of this material fro-m various varieties of plants, it has long been desired to provide an economical means of chemically synthesizing this material, thereby eliminating the necessity ofisolating this material from its natural source.

wherein R is as above,

by first treating the compound of the formula II with a hydrohalic acid in the presence of metal halide to form a compound of the formula:

III

wherein X is a halogen and R is as above.

- The compound of formula-III is treated with potassium t-amylate in the presence of an aromatic solvent to produce the compound of formula I.

In addition to producing the naturally occurring products of formula I-A above, which have known bactericidal, sedative, analgesic and psychotomimetic properties, the process of this invention produces new and novel pyrans of the formula:

wherein R is hydrogen, halogen or alkyl having from 1 to 10 carbon atoms with the proviso that when R is n-amyl, R is not substituted in the 3-position of the dibenzo(b,d)-pyran ring.

The novel compounds of formula I-B exhibit psychoto mimetic, analgesic, sedative and bactericidal'properties in like manner as the naturally occurring compounds of formula I-A a bove.

3 DETAILED DESCRIPTION The numbering of the rings in compounds of the formulae I, LA, 143, H and III is shown for the purpose of convenience. As used throughout the application, the term alkyl comprehends both straight and branched chain alkyl groups containing from 1 to 10 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, nheptyl, n-octyl, etc. In accordance with a preferred embodiment of this invention, R is an alkyl residue situated in the 3-position of the compound of formula I above. The term halogen includes all four halogens, i.e., chlorine, bromine, fluorine and iodine with chlorine and bromine being preferred.

The compounds of formula I above, are useful as psychotomirnetic agents, sedatives and analgesics. The compounds of formula I above are used in the form of conventional pharmaceutical preparations which contain said compounds in connection with conventional pharmaceutical organic or inorganic carrier materials suitable for internal administration. The pharmaceutical compositions containing the compounds of formula I above can be administered parenterally or orally, dosages can be adjusted to individual requirements, for example, these compounds can be administered in dosages of from about 0.1 mg./kg. to about 5 mg./kg. per day. These dosages can be administered in a single dosage form or in divided dosage forms. The pharmaceutical compositions can contain such conventional organic or inorganic inert carrier materials as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, Vaseline or the like. The pharmaceutical preparations can be in the conventional solid forms such as tablets, dragees, suppositories, capsules or in conventional liquid form such as solutions, suspensions or emulsions. The pharmaceutical compositions can be submitted to conventional pharmaceutical expedients such as sterilization and/or can contain conventional pharmaceutical additives such as preservatives, stabilizing agents, wettng agents, emulsifying agents, salts for adjustng the osmotic pressure, buffers or the like. They can also contain other therapeutically useful materials.

The compounds of formula H can be synthesized by condensing in the presence of an acid agent, a resorcinol of the formula:

wherein R is as above,

with either 1,5,8-mcnthatriene which has the formula:

CHg- =CH3 8 9 V or with p-menthadien (2,8)-ol-(1) which has the general formula:

tane, S-n-propyl resorcinol, S-methyl resorcinol (orcinol), S-n-pentyl resorcinol (olivetol), 5-(1-methylbutyl)-resorcinol, S-n-hexylresorcinol, 5-(l-ethylbutyD-resorcinol, 5- 1,1-dimet-hyl-butyl) -resorcinol, 5 1,2-dimethylbutyl) -resorcinol, S-n-heptyl-resorcinol, 5-(1-methyl-hexyl) resorcinol, S-n-octylresorcinol, 5-(l-n-propylpentyl)-resorcinol, 5-( l-methyloctyl)-resorcinol and the like.

The compounds of formula I above, as is evident from the structural configuration thereof, can be optically active as well as stereospecific about the 6a,l0a-positions. Any of the isomers of ('+)-p-men-thadien-ol-(1) of formula VI above which are (+)-cis and (-+)-trans-p-methadienol- (l) as well as the racemic mixture thereof can be utilized in the process of this invention to produce the compounds of formula I above. The optical configuration about the 4- position of the compound of formula V or VI used as one of the starting materials will determine the optical configuration about the 6a,10a-positions of the end products of formula I. Ihus, by employing the appropriate starting materials of formulae V or VI above there can be obtained a racemic mixture of a compound of formula I or the optically active -)-antipode.

In a preferred embodiment of the present invention starting materials of formulae V or VI are employed which result in the product of the optically active antipode. In a most preferred embodiment, appropriate starting materials of formulae V or VI are employed so that their reaction with a compound of formula IV and subsequent treatment with a hydrogen halide and then with potassium t-amylate in the presence of an aromatic solvent results in the formation of a compound of the formula wherein R is hydrogen, halogen, an alkyl radical having from 1 to 4 carbon atoms, or an alkyl radical having from 6-10 carbon atoms.

The novel preferred compounds of formula 10 exhibit sedative activity.

The condensation of compounds of the formula IV with compounds of the formulae V or VI can be carried out in a conventional inert solvent. Among the preferred solvents are included aliphatic or aromatic hydrocarbons such as petroleum ether, benzene, toluene, etc.; halogenated aliphatic or aromatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, chlorobenzene, etc.; nitrated hydrocarbons such as nitrobenzene, etc.; and ethers such as diethyl ether, tetrahydrofuran, dioxan, etc. Among the other conventional solvents which are preferred to be utilized in the process of this invention are included dimethylformamide, dimethylsulphoxide, or liquid sulphur dioxide.

The reaction to produce the compound of formula II above is carried out in the presence of any conventional organic or inorganic acid agents. Among the preferred acid agents which can be utilized in carrying out the process of this invention are included Lewis acids such as boron triiluoride, zinc chloride, aluminum chloride, tin tetrachloride, etc.; mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, polyphosphoric acids, etc.; and organic acids such as p-toluene sulphonic acid, methane sulphonic acid, formic acid, glacial acetic acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid, maleic acid etc. Sulphur dioxide can be utilized as both the acid medium and the organic solvent. Therefore, when liquid sulphur dioxide is utilized as the solvent medium, the reaction of this invention will take place without the addition of any other acid agent.

In carrying out the reaction to produce the compound of formula II above, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. If desired, lower or elevated temperatures can be utilized. This condensation reaction is advantageously eifected at a temperature of from about 0 C. to about 120 C. In a preferred embodiment of this invention, the reaction is particularly preferably carried out in the presence of b-toluene-sulphonic acid in benzene by heating to a temperature of about 80 C. for two hours under reflux conditions.

The compounds of formula IH above are prepared from the compound of formula II above by treating the compound of formula II above with a hydrohalic acid in the presence of a metal halide. In this reaction, the halide group of the metal halide should be the same as the halide group of the acid halide. The metal halide can be formed from any Group II metal, Group IH and Group IV metal of the periodic chart. Among the metal halides which can be utilized are included aluminum bromide, aluminum chloride, stannic chloride, boron trifiuoride, magnesium chloride, titanium chloride, ferric chloride, etc. The preferred metal halide utilized in accordance with this invention is zinc chloride. Any conventional hydrohalic acid such as hydrochloric, hydrobromic, etc. can be utilized. Generally, this reaction is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. The preferred solvents are the halogenated hydrocarbon solvents such as methylene chloride. In carrying out this reaction, temperature and pressure are not critical, and this reaction can be carried out at room temperature and atmospheric pressure. If desired, elevated or lower temperatures can be utilized.

In accordance with a preferred embodiment of this invention, the compound of the formula II above is converted to a compound of the formula III above by treating the compound of the formula II above with zinc chloride in a methylene chloride solution saturated with hydrogen chloride.

In accordance with this invention, compounds of formula III above where R is a halo group such as bromine or chlorine are new and novel compounds. In accordance with a preferred embodiment of this invention, R is a halo group substituted in the 3-position of the benzo(b,d)-pyran ring of the compound of formula III above.

The conversion of compounds of the formula H above to compounds of the formula I above, is accomplished by treating the compounds of the formula III with potassium t-amylate in the presence of an inert aromatic hydrocarbon solvent. Any conventional aromatic hydrocarbon solvent can be utilized. Among the preferred aromatic hydrocarbon solvents are included toluene, benzene, xylene, etc. The preferred solvent is benzene. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. If desired, elevated or reduced temperatures and pressures can be utilized. However, temperatures as low as 0 C. and as high as 100 C. can be utilized depending upon the freezing and boiling point of the solvent. However, it is generally preferred to carry out the reaction at a temperature of 50 C. to 70 C.

As indicated above, the novel compounds of formula IC exhibit sedative activity. The sedative activity of the novel (-)-antipode of the formula IC compounds can be demonstrated utilizing the hypnotic potentiation test, which test measures the potentiation of the hypnotic effect of a sub-hypnotic dose of pentobarbitone. The hynotic potentiation test is conducted as follows:

In a preliminary test, 100 mg./kg. of the compound is administered orally to each of a group of 6 animals (male rats). One hour later, the animals are given a subhypnotic dose of sodium pentobarbitone (12.5 mg./kg.) intraperitoneally.

30 minutes later, the number (n) of animals having lost their righting-reflex for more than 1 minute is noted.

RESULTS If n is zero, the compound is considered inactive.

If n is between 1 and 6, the compound is subsequently studied at different dose levels in order to determine the ED and the ED by the graphic method, i.e. the dose at which 6 and 3 animals, respectively, out of 6 have lost their righting-reflex as described above. The results in the hypnotic potentiation test for representative compounds of formula IC as wellas for representative prior art compounds are shown in Table I. The representative compounds employed for this experimentation are:

( )-1-Hydroxy-3 1, 1-dimethylpentyl -6,6,9-trimethyl- 6a, l0a-trans-6a,7,8,10a-tetrahydro-dibenzo(b,d)-pyran [Compound A] )-l-Hydroxy-3-( l-methylpentyl) -6,6,9-trimethyl-6a,

10a-trans-6a,7,8,10a-tetrahydro-dibenzo(b,d)-pyran [Compound B] )-l-Hydroxy-3-( 1,2-dimethylheptyl) -6,6,9-trimethyl- 6a, 10a-trans-6a,7,8, 1 Oa-tetrahydro-dibenzo (b,d)-pyran [Compound C] l-Hydroxy-3 -n-pentyl-6, 6,9-trimethyl-6a, 10a-trans- 6a,7,8, IOa-tetrahydro-dibenzo (b,d) -pyran [Compound Dnaturally occurring compound disclosed in J. Am. Chem. Soc., 86, 1646 (1964) and J. Am. Chem. Soc., 88, 367 (1966)] Rac.-l-Hydroxy-3-( l-methylpentyl) -6,6,9-trimethyl-6a,

7,8, l 0a-tetrahydro-6H-dibenzo(b,d) -pyran [Compound E-disclosed in U.S. Pat. No. 3,3 88,136] and Rac.-1-Hydroxy-3-( 1,2-dimethyl-heptyl) -6,6,9-trimethyl- 6a,7,8, l0a-tetrahydro-6H-dibenzo- (b,d -pyran [Compound F-disclosed in U.S. Pat. No. 3,388,136].

TABLE I.HYPNOTIC POTENTIATION C Hs-CH-(f H-C 5H1! C ompound C TABLE IContiuued Compound ED mg.lkg., p.o.

H CHz-CH J-CH:

CH| HCIHH Compound F The following examples are illustrative but not limitative of this invention. All temperatures are in degrees centigrade. The ether utilized in the examples is diethyl ether. The pressure utilized in the examples is expressed as mm. Hg.

EXAMPLE 1 A solution of 360 mg. of olivetol and 270 mg. of (i)- p-menthatriene-(l,5,8) in 7 ml. of liquid sulphur dioxide is allowed to stand at room temperature for 24 hours in a sealed tube. The sulphur dioxide is thereupon evaporated off under a calcium chloride tube. The oily residue is dissolved in diethyl ether. The ether solution is extracted once with dilute sodium hydrogen carbonate and dried over sodium sulphate. After evaporation of. the ether, 633 mg. of a yellow resin remains. The yellow resin which is obtained, is chromatographed on 20 g. of silica gel and upon elution with benzene and distillation at high vacuum, 168 mg. of (i) 1 hydroxy-3n-amyl-6,6,9-trimethyl- 6a, 10a trans 6a,7,10,10a-tetrahydrodibenzo (b,d)-pyran is obtained. The R value of the tetrahydrodibenzopyran obtained is 0.46; boiling point 140-150" C./0.00l mm. Hg. (silica gel thin layer chromatogram in chloroform).

EXAMPLE 2 A mixture of 450 mg. of olivetol, 380 mg. (+)-cisb menthadien (2,8) ol-(l) and 58 mg. of p-toluenesulphonic acid monohydrate in 25 ml. of benzene is boiled under reflux for 2 hours. The resulting orange-yellow solution is cooled in an ice-water bath and dissolved in diethyl ether. The other solution is immediately shaken once with dilute sodium hydrogen carbonate solution and once with sodium chloride solution. The almost completely decolorized ether solution is dried over sodium sulphate. After evaporation of the ether, 818 mg. of a light-yellow oil remained. The resulting yellow oil is chromatographed on 35 g. of silica gel and upon elution with benzene and 8 distillation at high vacuum, 384 mg. of (-)-1-hydroxy- 3n amyl 6,6,9 trimethyl 6a,l0a-trans-6a,7,l0,10atetrahydrodibenzo(b,d)-pyran is obtained.

EXAMPLE 3 A mixture of 474 mg. of olivetol, 403 mg. of trans-p-menthadien-(2,8)-ol(1) and mg. of p-toluenesulphonic acid monohydrate in 25 ml. of benzene is reacted in the manner of Example 2. There resulted 900 mg. of a yellow oil. The resulting yellow oil was chromatographed on 35 g. of silica gel and upon elution with benzene and distillation at high vacuum, 436 mg. of 1 hydroxy-3n-amyl-6,6,9-trimethyl-6a,10a-trans-6a,7,10, lOa-tetrahydrodibenzo(b,d)-pyran was obtained having a R value (silica gel thin layer chromatogram in chloroform) of 0.51; and a boiling point of -150 C./0.001 mm. Hg.

EXAMPLE 4 A mixture of 2.6 g. (13.4 mMol) of 2-(3,5-dihydroxyphenyl) hexane, 2.05 g. (13.4 mMol) of (+)-trans-pmenthadien-(2,8)-ol-(1) and 260 mg. (1.35 mMol) of p-toluenesulphonic acid monohydrate in 60 ml. of henzene is boiled under reflux for 2 /2 hours. The resulting orange solution is cooled in an ice-water bath and dissolved in diethyl ether. The ether solution is immediately shaken once with a dilute sodium hydrogen carbonate solution and once with a sodium chloride solution. The now almost completely colorless ether solution is dried over sodium sulphate. After evaporation of the ether there remains 4.85 g. of a light yellow oil. The resulting oil is chromatographed on 130 g. of silica gel and upon elution with a 1 to 1 by volume mixture of hexane and benzene and drying to constant weight, there is obtained (--)-1- hydroxy-3 [hexyl(2)]-6,6,9-trimethyl-6a,10a-trans-6a,7, 10,1021 tetrahydrodibenzo(b,d)-pyran. After distillation under high vacuum the product has an R value (silica gel chromatogram in chloroform) of 0.58 and a boiling point of 190 C./0.001 mm. Hg.

EXAMPLE 5 A mixture of 2.16 g. (9.15 mMol) of 2-(3,5-dihydroxyphenyl)-3-methyl octane, 1.4 g. (9.2 mMol) of (+)-trans-p-menthadien-(2,8)-ol-(1) and mg. (0.92 mMol) of p-toluene sulphonic acid monohydrate in 60 ml. of benzene is heated under reflux for 2% hours. The resulting solution is cooled with an ice-water bath and dissolved in diethyl ether. The ether solution is immediately shaken once with a dilute sodium hydrogen carbonate solution and once with a sodium chloride solution. The solution is then dried over sodium sulphate and after evaporation of the ether there remains 3.4 g. of a light yellow oil. The resulting yellow oil is chromatographed on 70 g. of silica gel and upon elution with 1 to 1 by volume mixture of hexane and benzene and drying to constant weight, 1-hydroxy-3-[3-methyloctyl(2)]-6,6,9-trimethyl 6a,10a-trans-6a,7,l0,10a-tetrahydrodibenzo(b,d)- pyran is produced. Upon distillation under high vacuum, this product has an R value (silica gel chromatogram in chloroform) of 0.55 and a boiling point of 190 C/ 0.001 mm. Hg.

EXAMPLE 6 2.84 g. (20 mMol) of orcinol-monohydrate is mixed with 3.05 g. (20 mMol) of (+)-trans-p-menthadien-*(2,8)- ol-(1) in 50 ml. of benzene and 0.39 g. (2 mMol) of ptoluene sulphonic acid monohydrate. This mixture is heated at reflux for 2 hours. The resulting reaction solution is added to 50 ml. of diethyl ether and extracted once with a dilute sodium bicarbonate solution. The ether phase is dried over sodium sulphate and the ether is evaporated. There results 5.6 g. of a yellow oil which is chromatographed on g. of silica gel and eluted with benzene. The eluted solution is distilled at high vacuum yielding 2350 mg. of (-)-1-hydroxy-3,6,6,9-tetramethyl- 6a,10a trans-6a,7,10,10a-tetrahydrodibenzo( b,d)-pyran.

This compound has an R;- value of 0.48 and a boiling point of 130l40 C./0.001 mm. Hg.

EXAMPLE 7 A solution of 0.427 g. (2.37 mMol) of olivetol and 0.356 g. (2.34 mMol) of (+)-t.rans-p-menthadien-(2,8)- ol-(l) in liquid sulphur dioxide is allowed to stand at room temperature for 70 hours in a sealed tube. Thereafter, the solvent medium is carefully distilled off. The residue is dissolved in 50 ml. of diethyl ether. The ether solution is extracted once with a dilute sodium bicarbonate solution. After extraction, the ether solution is dried and evaporated. The dry residue (0.74 g.), which is obtained is chromatographed on silica gel and eluted.

One obtains after distillation utilizing a high vacuum, 142 mg. of ()-1-hydroxy-3-n-amyl-6,6,9-trimethyl-6a, la-trans-6a,7,10,10a-tetrahydordibenzo(b,d)-pyran. This compound has an R value (silica gel thin layer chromatogram in chloroform) of 0.51 and a boiling point of 140- 150 C./0.001 mm. Hg.

EXAMPLE 8 0.595 g. (3.3 mMol) olivetol is mixed with 0.502 g. (3.3 mMol) (+)-cis-p-menthadien-(2,8-)-ol-(1) in 8 ml. of liquid sulphur dioxide. This mixture is allowed to stand at room temperature for 120 hours in a sealed tube. After working up the mixture in the manner described in Example 1, 1.085 g. of an oily residue is obtained. The oil is chromatographed over silica gel and eluted. Upon distillation in high vacuum, 215 mg. of (--)-1-hydroxy-3-namyl 6,6,9 trimethyl-6a,10a-trans-6a,7,10,10a-tetrahydrodibenzo(b,d)-pyran is obtained. This compound has an R value (silica gel thin layer chromatogram in chloroform) of 0.52 and a boiling point of 140-150 C./0.001 mm. Hg.

EXAMPLE 9 A mixture of 0.54 g. (3 mMol) of olivetol, 0.46 g. (3 mMol) of (+)-trans-p-menthadien-(2,-8)-ol-(1) and 0.5 ml. of trifiuoro acetic acid in 50 ml. of benzene is refluxed for hours. The resulting solution is worked up in the manner of Example 2 to yield 0.95 g. of a residue. The resulting residue is chromatographed on silica gel and upon elution and distillation at high vacuum yields 520 mg. of ()-1-hydroxy-3-n-amyl-6,6,9-trimethyl-6a, 10a-trans-6a,7,10,10a-tetrahydrodibenzo(b,d)-pyran. This compound has an R value (silica gel thin layer chromatogram in chloroform) of 0.52 and a boiling point of 140- 150 C./0.001 mm. Hg.

EXAMPLE 10 A mixture of 2.2 g. (20 mMol) of crystalline resorcinol, 3.05 g. (20 mMol) (+)-trans-p-menthadien (2,8)-ol-(l) and 0.4 g. (2 mMol) of p-toluene sulphonic acid monohydrate in 50 ml. of benzene is heated under reflux for 2 hours. The resulting solution is dissolved in 50 ml. of diethyl ether. The ether is extracted once with dilute sodium bicarbonate solution. The ether phase is dried and evaporated. 5.1 g. of a yellow oil is obtained. This oil is chromatographed on 150 g. of silica gel and eluted with benzene. After distilling off the benzene under high vacuum, there is obtained 778 mg. of ()-1-hydroxy-6,6,9-trimethyl-6a,10a-trans-6a,7,10,10a tetrahydrodibenzo (b,d)- pyran. This compound has an R value (silica gel thin layer chromatogram in chloroform) of 0.35 and a boiling point of 155 C./ 0.001 mm. Hg.

EXAMPLE 11 A. Preparation of (-)-1-hydroxy-3-n-amy1-6,6,9-trimethyl-6a,10a-trans-6a,7,8,IOa-tetrahydro dibenzo(b,

d)-pyran 1.080 g. (3.1 mMol) of oily ()-l-hydroxy-3n-amy1-9- chloro-6,6,9-trimethyl-6a,-10a-trans-6a,7,8,9,10,10a hexahydro-dibenzo(b,d)-pyran is dissolved in 15 ml. of absolute benzene. The resulting solution is added dropwise under stirring and under an atmosphere of argon to a 10 ml. solution of 1-M potassium t-amylate in absolute benzene which is cooled to 5 C. After the dropwise addition, the yellow reaction solution is heated for 15 min. at 65 C. and then cooled with ice. After the solution is cooled, carbon dioxide is fed into the solution for approximately 30 minutes causing a partial decolorization of the solution. The solution is partitioned between ml. of ether and 80 ml. of ice water, the pH of the solution being neutralized to 7 by addition of a sodium bicarbonate solution. The ether phase is dried over sodium sulphate and evaporated. After drying in high vacuum at 0.001 mm. Hg there remains 970 mg. ()-1-hydroxy-3-n-amyl-6,6,9-trimethyl- 6a,10a-trans-6a,7,8,10a-tetrahydro-dibenzo(b,d) pyran. [oz] =-150.5 (c.=0.53/CHCl B. Preparation of (-)-1-hydroxy-3-n-amyl-9-chloro-6,6,

9-trimethyl-6a,10a-trans-6a,7,8,9,10,10a hexahydrodibenzo(b,d)-pyran The (-)-1-hydroxy-3-n-amyl-9-chloro-6,6,9-trimethyl- 6a,10a-trans-6a,7,8,9,10,10a hexahydro dibenzo(b,d)- pyran used as the starting product is manufactured as follows:

A solution of 1.046 g. (3.3 mMol) of oily ()-1-hydroxy-3-n-amyl-6,6,9-trimethyl-6a, IOa-trans 621,7, 10, 10atetrahydro-dibenzo(b,d)-pyran which has been dried in high vacuum in 20 ml. of absolute methylene chloride is treated with 300 mg. of anhydrous zinc chloride. The colorless mixture is saturated with hydrogen chloride at 0 in a drier apparatus and closed overnight at room temperature and allowed to react with stirring. All of the oil has gone into solution after 15 hours. The now deep yellow solution has added thereto 80 ml. of methylene chloride. After addition, this mixture is treated once with 80 m1. of ice-water and then with sodium bicarbonate solution up to incipient precipitation of zinc hydroxide. After this treatment, the mixture is extracted once with 50 ml. of water. The almost colorless methylene chloride phase is dried over sodium sulphate and evaporated at room temperature. After drying in high vacuum, there is produced 1.120 g. of oily (-)-1-hydroxy-3-n-amyl-9- chloro-6,6,9-trimethyl-6a,10a-trans-6a,7,8,9,10,10a hexahydro-dibenzo(*b,d)-pyran. [a] =78.5 (c.=0u28 in chloroform).

EXAMPLE 12 1.00 g. of (-)-l-hydroxy3-[hexyl(2)]-9-chloro-6,6,9- trimethyl-6a,10a-trans-6a,7,8,9,910,10a hexahydro dibenzo(b,d)-pyran is dissolved in 10 ml. of absolute benzene. This solution is added dropwise under an atmosphere of argon to 10 ml. of l-M potassium t-amylate in absolute benzene, cooled to a temperature of 5. After this dropwise addition, the resulting yellow solution is heated for 15 min. at 65 C. and then cooled with ice. After cooling, carbon dioxide is fed into the solution for approximately 30 minutes, causing a partial decolorization of the solution. The solution is then partitioned between 80 ml. of ether and 80 ml. of ice-water, the pH of the solution being neutralized to 7 by addition of a sodium bicarbonate solution. The ether phase is dried over sodium sulphate and evaporated. After drying in high vacuum at 0.001 mm., there resulted 0.90 g. (-)-1-hydroxy-3-[hexyl(2)]- 6,6,9-trimethyl-6a,10a-trans-6a,7,8,IOa-tetrahydro-dibenzo (b,d)-pyran. [a] =--146 (c.=0.46 in ethanol).

The ()-1-hydroxy-3-[hexyl(2)]-9-chloro-6,6,9 trimethy1-6a,10a-trans-6a,7 ,8,9,10,10a hexahydro dibenzo (b,d)-pyran used as a starting material is manufactured according to the procedure in Example 11-B from (-)-1- hydroxy-3-[hexyl(2) ]-6,6,9-trirnethyl-6a,IOa-trans 6a,7, 10,10a-tetrahydro-dibenzo(b,d)-pyran, by treatment with zinc chloride and hydrochloric acid in methylene chloride. This product exhibits the following characteristic data: [a] =-73.0 (c.=2.3 in chloroform).

1 l EXAMPLE 13 '()-1-hydroxy-3-[3-methyl octyl(2)]-9-chloro 6,6,9- trimethyl-6a,l0a-trans-6a,7,8,9,10,10ahexahydro dibenzo (b,d)-pyran is converted by the procedure of Example 12 into -1-hydroxy-3-[3-methyloctyl(2) ]-6,6,9-trimethyl- 6a,10a-trans-6a,7,8,IOa-tetrahydto-dibenzo(b,d) pyran: {at} 128.0 (c.=0.49 in ethanol).

The starting material ()-l-hydroxy-3-[3-methyloctyl (2)]-9-chloro-6,6,9-trimethyl-6a,10a trans 6a,7,8,9,10, 10a-hexahydro-dibenzo (b,d) -pyran, is prepared from (-)-1-hydroxy-3-[3-methyloctyl(2) ]-6,6,9-trimethyl 6a, la-trans-6a,7,10,10a-tetrahydro-dibenzo (b,d) pyran, utilizing zinc chloride and hydrochloric acid in methylene chloride by means of the procedure outlined in part B of Example 11. The physical constants for this startingmaterial are: [u] =62.0 (c.=0.39 in chloroform).

EXAMPLE 14 300 mg. of oily ()-l-hydroxy-3[Z-methylhexyl-(Z)]- 9-chloro-6,6,9-trimethyl 6a,10a trans-6a,7,8,9,10,l0ahexahydro-dibenzo(b,d)-pyran is dissolved in ml. of absolute benzene. The thus obtained solution is added dropwise under constant stirring to 5 ml. of a solution of l-M potassium-t-amylate dissolved in benzene. During the dropwise addition, the solution of potassium-tamylate is maintained under an atmosphere of argon. After this addition, a dark red solution is obtained. The resulting mixture is heated to 65 C. for 15 min., then cooled with ice and at this temperature, carbon dioxide is bubbled into the solution for approx. 30 minutes. A partial decolorization of the solution occurs after this addition. After this addition, the solution is extracted with ether. The ether phase is dried and evaporated. After drying in high vacuum at 0.001 mm. Hg for 12 hours at 20 C. there remains 271 mg. of (-)-l-hydroxy-3[2- methylhexyl-(2)]-6,6,9-trimethyl 6a,10a trans-6a,7,8, a-tetrahydro-dibenzo(b,d) pyran. [u] -='l71.3 (c. =0.29' in chloroform).

The starting material -)-1-hydroxy-3-[2-methylhexyl-(2g)]-9-chloro 6,6,9 trimethyl-Sa,10a-trans-6a,7, 8,9,10,10a-hexahydrodibenzo(b,d)-pyran is prepared by the following procedure:

A mixture of 350 mg. of 2-(3,5-dihydroxyphenyl)-2- methylhexane, 260 mg. +)-trans-p-menthadien-(2,8)-01- (1) in 20 ml. of benzene is boiled under reflux with 40 mg. of p-toluene sulphonic acid monohydrate for 2% hours. The reaction solution is thereafter cooled with ice. A small amount of an aqueous solution of sodium bicarbonate is added to the cooled reaction solution. The condensation product is extracted from the reaction solution with diethyl ether. The extract is dried and evaporated. After drying and evaporating, 640 mg. of a yellow oil remains. The yellow oil, which is obtained, is chromatographed on 20 g. of silica gel. Upon elution with benzene and distillation at high vacuum there is obtained 535 mg. of 1 hydroxy-3-[2-methylhexyl-(2)]-6,6,9-trimethyl-6a,l0a-trans 6a,7,10,10a tetrahydIo-dibenzo (b,d)-pyran. The R value of the tetrahydro-dibenzo pyran obtained is 0.59 (silica gel thin layer chromatogram in chloroform). The boiling point of this compound is 170 C./0.001 mm. Hg.

330 mg. of oily (-)-l-hydroxy-3-[2-methylhexyl- (2)]-6,6,9-trimethyl 6a,10a trans-6a,7,10,10a-tetrahydro-dibenzo (b,d)-pyran is dissolved in 25 ml. of absolute methylene chloride. To this solution there is added 100 mg. of anhydrous zinc chloride. The mixture is saturated with hydrogen chloride at 0 C. The apparatus containing this mixture is closed and the saturated mixture is allowed to react overnight while it is maintained under constant stirring and at room temperature. After this period, the reaction solution is diluted with methylene chloride and then treated with ice water. After treating with ice water, sodium bicarbonate solution is added to the mixture in an amount up to the incipient precipitation of the zinc hydroxide. The methylene chloride phase is dried and evaporated. After drying in high vacuum, 0.001 mm. Hg. at 20 C. for 12 hours, there remains 362 mg. of (-)-1-hydroxy-3-[2-methylhexyl-(2)-9- chloro-6,6,9-trimethyl 6a,10a trans-6a,7,8,9,10,l0ahexahydro-dibenzo(b,d)-pyran. This pyran has an R value (silica gel thin layer chromatogram in chloroform) of 0.63 and [a] -=-70.5 (c.=0.69 in chloroform).

EXAMPLE 15 A solution containing mg. (-)-1-hydroxy-3,9-dichloro 6,6,9 trimethyl 6a,10a trans-6a,7,8,9,l0,l0ahexahydro-dibenzo(b,d)-pyran in 5 ml. of absolute benzene is added dropwise under an atmosphere of argon to a 2 ml. solution of l-M potassium-t-amylate in absolute benzene. The solution of potassiumt-amylate is maintained at 5 C. and constantly stirred during the addition. After the addition is complete, the mixture is warmed to 65 C. for 15 minutes. The resulting orange solution is cooled with ice and carbon dioxide is subsequently bubbled therein for approximately 30 minutes. During the addition of the carbonic acid, decolorization of the solution occurs. Thereafter, the solution is extracted with ether. The ether extract is neutralized to a pH of 7 by the addition of a sodium bicarbonate solution. The ether phase is dried over the sodium sulfate and evaporated. After drying in high vacuum at 0.001 mm. Hg there produced 123 mg. of (-)-l-hydroxy-3-chloro-6,6,9-tr1 methyl-6a,l0a-trans 6a,7,8,10a tetrahydro dibenzo (b,d)-pyran. This pyran has an R value of 0.33 (silica gel thin layer chromatogram in chloroform) and [a] =166.2 (c.=0.35 in chloroform).

The starting material '(---)-l-hydroxy-3,9-dichloro- 6,6,9-trimethyl-6a,l0a-trans 6a,7,8,9',10,l0a hexahydrodibenzo(b,d)-pyran is produced by the following procedure.

280 mg. of S-chloro-resorcinol is mixed with 300 mg. of (+)-trans-p-menthadien-(2,8)-ol-(1) dissolved in 20 m1. of benzene. This mixture is refluxed for 2 hours with 40 mg. of p-toluene-sulphonic acid monohydrate. Thereafter, the solution iscooled in ice. After cooling the solution in ice, diethyl ether and a dilute sodium bicarbonate solution are added thereto. The ether phase which results is dried and evaporated. The resulting residue is chromatographed on 30 g. of silica gel and upon elution with benzene and distillation at high vacuum there is ob tained 130 mg. of ()-1-hydroxy-3-chloro-6,6,9-trimethyl-6a,10a-trans 6a,7,10,10a tetrahydro-dibenzo (b,d)-pyran. This pyran has a boiling point of 170 C;/ 0.001 mm. Hg and an R value (silica gel thin layer chromatogram in chloroform) of 0.35; [a] =278 (c.=0.l3 in chloroform).

mg. of (--)-1-hydroxy-3-chloro-6,6,9-trimethyl- 6a,10a-trans 6a,7,10,10a tetrahydro-dibenzo(b,d)pyran dissolved in 20 ml. of absolute methylene chloride has 50 mg. of anhydrous zinc chloride added thereto. The resulting mixture is saturated with hydrogen chloride at 0 C. This saturated mixture is allowed to remain overnight at room temperature. The resulting yellow solution is diluted with methylene chloride. The diluted solution is treated once with sodium bicarbonate solution in an amount up to the incipient precipitation of zinc hydroxide. Following the extraction, the resulting organic phase is dried and evaporated. After drying at high vacuum, 171 mg. of (-)-1-hydroxy-3,9-dichloro-6,6,9 trimethyl 6a,10atrans-6a,7,8,9,l0,10a hexahydro-dibenzo(b,d)-pyran is obtained.

EXAMPLE 16 790 mg. of -)-1-hydroxy-3,6,6,9-tetramethyl-9-chlor0 6a,10a trans 6a,7,8,9,10,10a hexahydro-dibenzo- (b,d)-pyran dissolved in 15 ml. of absolute benzene is added dropwise to a soltuion of 10 ml. of l-M potassium t-amylate in absolute benzene. This addition is carried out under an atmosphere of argon while the potassium t-amylate solution is constantly stirred and cooled by means of ice water. After the addition, the reaction solution is heated for 15 min. to a temperature of from (SS-70 C. After cooling with ice, carbon dioxide is bubbled into the solution for approximately 30 minutes. The mixture is partitioned between ether and ice water. The pH of the mixture is neutralized to 7 by the addition of a sodium bicarbonate solution. The ether phase is dried and distillation under high vacuum produces 690 mg. of ()-1- hydroxy-3,6,6,9-tetramethyl 6a,l0a trans 6a,7,8,l0atetrahydro-dibenzo(b,d)-pyran. This product is in the form of a yellow oil with an R value (silica gel thin layer chromatogram in chloroform) of 0.46 and a boiling point of 160 C./0.001 mm. Hg [a] =229 (c. =0.4/ CHCl The starting material (.)-1-hydroxy 3,6,6,9 tetramethyl-9-chloro-6a,IOa-trans 6a,7,8,9,10,10a hexahydro-dibenzo(b,d)-pyran is produced in the manner of part B of Example 11 from ---)-1-hydroxy-3,6,6,9-tetramethyl-6a,l0a trans 6a,7,10,10a tetrahydrodibenzo(b,d)- pyran. This starting material has [a] =.98.4 (c.=0.25/CHC1 wherein X is a halogen and R is hydrogen or halogen, said dibenzopyran being in substantially pure form and being substantially free from its (+)-optical antipode.

2. A dibenzopyran of the formula:

wherein R is a halogen.

3. The compound of claim 2 wherein R is chlorine. 4. The (')-antipode of a dibenzopyran of the formula wherein R is halogen.

14 5. A compound according to claim 4 wherein R is chlorine.

6. The compound (--)-1-hydroxy-3,9-dichloro-6-6-9- trimethy1-6a,10a trans 6a,7,8,9,10,10a hexahydrodi- 5 benzo(b,d)-pyran.

7. The ('-)-antipode of a dibenzopyran of the formula:

said dibenzopyran being in substantially pure form and being substantially free from its -H-optical antipode.

said dibenzopyran being in substantially pure form and being substantially free from its (=+)-optical antipode.

9. The (-)-antipode of a dibenzopyran of the forsaid dibenzopyran being in substantially pure form and being substantially free from its B-optical antipode.

References Cited UNITED STATES PATENTS 3,388,136 6/1968 Taylor et al 260-345.3 3,507,885 4/1970 Fahrcnholtz 260-345.3 3,576,887 4/1971 Hughes et al. 260345.3 x

55 OTHER REFERENCES Gaoni et al.: J. Am. Chem. Soc., vol. 86, pp. 1646-7 (1964).

JOHN M. FORD, Primary Examiner 60 US. Cl. X.R. 

